Natural and acquired immunity

Every animal species possesses some natural resistance to disease. Humans have a high degree of resistance to foot-and-mouth disease, for example, while the cattle and sheep with which they may be in close contact suffer in the thousands from it. Rats are highly resistant to diphtheria, whereas unimmunized children readily contract the disease.

What such resistance depends on is not always well understood. In the case of many viruses, resistance is related to the presence on the cell surface of protein receptors that bind to the virus, allowing it to gain entry into the cell and thus cause infection. Presumably, most causes of absolute resistance are genetically determined; it is possible, for example, to produce by selective breeding two strains of rabbits, one highly susceptible to tuberculosis, the other highly resistant. In humans there may be apparent racial differences, but it is always important to disentangle such factors as climate, nutrition, and economics from those that might be genetically determined. In some tropical and subtropical countries, for example, poliomyelitis is a rare clinical disease, though a common infection, but unimmunized visitors to such countries often contract serious clinical forms of the disease. The absence of serious disease in the residents is due not to natural resistance, however, but to resistance acquired after repeated exposure to poliovirus from infancy onward. Unimmunized visitors from other countries, with perhaps stricter standards of hygiene, are protected from such immunizing exposures and have no acquired resistance to the virus when they encounter it as adults.

Natural resistance, in contrast to acquired immunity, does not depend upon such exposures. The human skin obviously has great inherent powers of resistance to infection, for most cuts and abrasions heal quickly, though often they are smothered with potentially pathogenic microorganisms. If an equal number of typhoid bacteria are spread on a person’s skin and on a glass plate, those on the skin die much more quickly than do those on the plate, suggesting that the skin has some bactericidal property against typhoid germs. The skin also varies in its resistance to infectious organisms at different ages: impetigo is a common bacterial infection of children’s skin but is rarer in adults, and acne is a common infection of the skin of adolescents but is uncommon in childhood or in older adults. The phenomenon of natural immunity can be illustrated equally well with examples from the respiratory, intestinal, or genital tracts, where large surface areas are exposed to potentially infective agents and yet infection does not occur.

If an organism causes local infection or gains entry into the bloodstream, a complicated series of events ensues. These events are described in detail in the article immune system, but they can be summarized as follows: special types of white blood cells called polymorphonuclear leukocytes or granulocytes, which are normally manufactured in the bone marrow and which circulate in the blood, move to the site of the infection. Some of these cells reach the site by chance, in a process called random migration, since almost every body site is supplied constantly with the blood in which these cells circulate. Additional granulocytes are attracted and directed to the sites of infection in a process called directed migration, or chemotaxis.

When a granulocyte reaches the invading organism, it attempts to ingest the invader. Ingestion of bacteria may require the help of still other components of the blood, called opsonins, which act to coat the bacterial cell wall and prepare it for ingestion. An opsonin generally is a protein substance, such as one of the circulating immunoglobulins or complement components.

Once a prepared bacterium has been taken inside the white blood cell, a complex series of biochemical events occurs. A bacterium-containing vacuole (phagosome) may combine with another vacuole that contains bacterial-degrading proteins (lysozymes). The bacterium may be killed, but its products pass into the bloodstream, where they come in contact with other circulating white blood cells called lymphocytes. Two general types of lymphocytes—T cells and B cells—are of great importance in protecting the human host. When a T cell encounters bacterial products, either directly or via presentation by a special antigen-presenting cell, it is sensitized to recognize the material as foreign, and, once sensitized, it possesses an immunologic memory. If the T cell encounters the same bacterial product again, it immediately recognizes it and sets up an appropriate defense more rapidly than it did on the first encounter. The ability of a T cell to function normally, providing what is generally referred to as cellular immunity, is dependent on the thymus gland. The lack of a thymus, therefore, impairs the body’s ability to defend itself against various types of infections.

After a T cell has encountered and responded to a foreign bacterium, it interacts with B cells, which are responsible for producing circulating proteins called immunoglobulins or antibodies. There are various types of B cells, each of which can produce only one of the five known forms of immunoglobulin (Ig). The first immunoglobulin to be produced is IgM. Later, during recovery from infection, the immunoglobulin IgG, which can specifically kill the invading microorganism, is produced. If the same microorganism invades the host again, the B cell immediately responds with a dramatic production of IgG specific for that organism, rapidly killing it and preventing disease.

In many cases, acquired immunity is lifelong, as with measles or rubella. In other instances, it can be short-lived, lasting not more than a few months. The persistence of acquired immunity is related not only to the level of circulating antibody but also to sensitized T cells (cell-mediated immunity). Although both cell-mediated immunity and humoral (B-cell) immunity are important, their relative significance in protecting a person against disease varies with particular microorganisms. For example, antibody is of great importance in protection against common bacterial infections such as pneumococcal pneumonia or streptococcal disease and against bacterial toxins, whereas cell-mediated immunity is of greater importance in protection against viruses such as measles or against the bacteria that cause tuberculosis.

Immunization

Antibodies are produced in the body in response to either infection with an organism or, through vaccination, the administration of a live or inactivated organism or its toxin by mouth or by injection. When given alive, the organisms are weakened, or attenuated, by some laboratory means so that they still stimulate antibodies but do not produce their characteristic disease. However stimulated, the antibody-producing cells of the body remain sensitized to the infectious agent and can respond to it again, pouring out more antibody. One attack of a disease, therefore, often renders a person immune to a second attack, providing the theoretical basis for active immunization by vaccines.

Antibody can be passed from one person to another, conferring protection on the antibody recipient. In such a case, however, the antibody has not been produced in the body of the second person, nor have his antibody-producing cells been stimulated. The antibody is then a foreign substance and is eventually eliminated from the body, and protection is short-lived. The most common form of this type of passive immunity is the transference of antibodies from a mother through the placenta to her unborn child. This is why a disease such as measles is uncommon in babies younger than one year. After that age, the infant has lost all of its maternal antibody and becomes susceptible to the disease unless protective measures, such as measles vaccination, are taken. Sometimes antibody is extracted in the form of immunoglobulin from blood taken from immune persons and is injected into susceptible persons to give them temporary protection against a disease, such as measles or hepatitis A.

Generally, active immunization is offered before the anticipated time of exposure to an infectious disease. When unvaccinated people are exposed to an infectious disease, two alternatives are available: active immunization may be initiated immediately in the expectation that immunity can be developed during the incubation period of the disease, or passive immunity can be provided for the interim period and then active immunization given at an appropriate time. The antigens (foreign substances in the body that stimulate the immune defense system) introduced in the process of active immunization can be live attenuated viruses or bacteria, killed microorganisms or inactivated toxins (toxoids), or purified cell wall products (polysaccharide capsules, protein antigens).

There are five basic requirements for an ideal vaccine. The agents used for immunization should not in themselves produce disease. The immunizing agent should induce long-lasting, ideally permanent, immunity. The agent used for immunization should not be transmissible to susceptible contacts of the person being vaccinated. The vaccine should be easy to produce, its potency easy to assess, and the antibody response to it measurable with common and inexpensive techniques. Finally, the agent in the vaccine should be free of contaminating substances. It is also recognized, however, that vaccine transmissibility can be helpful—e.g., in the case of live polio vaccine, which can be spread from vaccinated children to others who have not been vaccinated.

The route by which an antigen is administered frequently determines the type and duration of antibody response. For example, intramuscular injection of inactivated poliomyelitis virus (Salk vaccine) generates less production of serum antibody and induces only a temporary systemic immunity; it may not produce substantial local gastrointestinal immunity and, therefore, may not prevent the carrying of the virus in the gastrointestinal tract. Live, attenuated, oral poliomyelitis virus (Sabin vaccine) induces both local gastrointestinal and systemic antibody production; thus, immunization by mouth is preferred.

The schedule by which a vaccine is given depends upon the epidemiology of the naturally occurring disease, the duration of immunity that can be induced, the immunologic status of the host, and, in some cases, the availability of the patient. Measles, for example, is present in many communities and poses a potential threat to many children over 5 months of age. A substantial number of infants, however, are born with measles antibody from their mothers, and this maternal antibody interferes with an adequate antibody response until they are between 12 and 15 months of age. Generally, the immunization of infants after the age of 15 months benefits the community at large. In measles outbreaks, however, it may be advisable to alter this schedule and immunize all infants between 6 and 15 months of age.

Diphtheria toxoid

The introduction of diphtheria toxoid in the early 20th century led to a dramatic reduction in the incidence of the disease in many parts of the world. Primary prevention programs consisting of communitywide routine immunization of infants and children have largely eliminated the morbidity and mortality previously associated with diphtheria. Although the reported annual incidence of diphtheria has been relatively constant since the 1960s, local epidemics continue to occur. A complacent attitude toward immunization in some nations largely reflects a lack of awareness of the public health hazard that can arise if the proportion of susceptible individuals is significant enough to allow renewed outbreaks. Also, adequate immunization does not completely eliminate the potential for transmission of the bacterium Corynebacterium diphtheriae. Carriage of C. diphtheriae in the nose or throat has been well documented in fully immunized persons who clearly may transmit the disease to susceptible individuals.

The vaccine—prepared by the treatment of C. diphtheriae toxin with formaldehyde—is available in both fluid and adsorbed forms, the latter being recommended. Diphtheria toxoid is also available combined with tetanus toxoid and pertussis vaccine (DPT), combined with tetanus toxoid alone (DT), and combined with tetanus toxoid for adults (Td). The Td preparation contains only 15 to 20 percent of the diphtheria toxoid present in the DPT vaccine and is more suitable for use in older children and adults.

Pertussis vaccine

The number of cases of pertussis (whooping cough), a serious disease that is frequently fatal in infancy, can be dramatically reduced by the use of the pertussis vaccine. The pertussis immunizing agent is included in the DPT vaccine. Active immunity can be induced by three injections given eight weeks apart.

Tetanus toxoid

The efficacy of active immunization against tetanus was illustrated most dramatically during World War II, when the introduction of tetanus toxoid among military personnel virtually eliminated the occurrence of the disease as a result of war-related injuries. Since then, the routine immunization of civilian populations with tetanus toxoid has resulted in the decreased incidence of tetanus. In the United States, for example, 50 or fewer cases of tetanus are reported each year, the majority of deaths occurring in persons more than 60 years of age. In virtually all cases, the disease has been reported in unimmunized or inadequately immunized individuals.

Because it provides long-lasting protection and relative safety in humans, tetanus toxoid has proved to be an ideal vaccine. Tetanus toxoid is available in both vaccine fluid and alum-precipitated preparations. Commercially, tetanus toxoid is available in DPT, Td, and T (tetanus toxoid, adsorbed) preparations. DPT is recommended for infants, while the Td form is recommended at 12 and again at 18 years of age and only once every 10 years thereafter. If a person sustains a wound prone to tetanus (such as a puncture wound or a wound contaminated with animal excreta), Td is given along with tetanus immune globulin (TIG) to prevent occurrence of the disease.

Polio vaccine

The value of primary prevention of disease through active immunization programs has been most convincingly demonstrated in the case of poliomyelitis. Before the vaccine was known, more than 20,000 cases of paralytic disease occurred in the United States alone every year. With use of the vaccine after 1961, the last case of transmission of wild-type poliomyelitis was in 1979. However, such achievement toward eliminating the clinical disease does not justify a casual attitude toward compliance with the recommended polio vaccine schedules. Low immunization rates are still evident in children in certain disadvantaged urban and rural groups, among which most of the cases of paralytic disease continue to occur. This is all the more important as international attempts to eradicate poliomyelitis are achieving remarkable success, with most nations of the world now polio-free.

An Afghan health worker dropping polio vaccine into the mouth of a child during a vaccination …

Shah Marai—AFP/Getty Images

Live trivalent oral poliovirus vaccine (OPV) is used for routine mass immunization but is not recommended for patients with altered states of immunity (for example, those with cancer or an immune deficiency disease or those receiving immunosuppressive therapy) or for children whose siblings are known to have an immune deficiency disease. Inactivated poliovirus vaccine (IPV) is used for immunodeficient or immunosuppressed patients and for the primary immunization of adults because of their greater susceptibility to paralytic disease. In 2000, as poliomyelitis eradication appeared imminent, the United States switched from OPV to IPV as a routine recommended infant vaccine.

Rubella (German measles) vaccine

A major epidemic in the United States in 1964 resulted in more than 20,000 cases of congenital rubella. In consequence, active immunization programs with attenuated rubella vaccine were initiated in 1969 in an attempt to prevent an expected epidemic in the early 1970s. The immunization of all children from 1 to 12 years of age was aimed at reducing the reservoir and transmission of wild rubella virus and, secondarily, at diminishing the risk of rubella infection in susceptible pregnant women. This national policy contrasts with that of the United Kingdom, where only girls from 10 to 14 years of age who do not have detectable antibody levels to rubella virus are immunized. Proponents of the British policy have argued that natural rubella infection, which confers lifelong immunity, is more effective than vaccine-induced protection of uncertain duration and that continued outbreaks of rubella in the United States (largely in older children and young adults) since the introduction of rubella vaccines attest to the difficulty of achieving herd (group) immunity for this disease.

Live attenuated rubella vaccine is available in combination with measles vaccine (MR) and in combination with measles and mumps vaccines (MMR). For routine infant immunization, MMR is given one time at about 15 months of age. Rubella vaccination can be accompanied by mild joint pain and fever in 5 percent of those who receive it. Vaccination is recommended for all children between the ages of 12 months and puberty. Vaccination is not recommended for pregnant women. A number of women, however, have inadvertently received rubella vaccine during pregnancy with no harm to their fetuses being noted.

Measles (rubeola) vaccine

The licensing and distribution of killed measles vaccine in 1963, followed by the development and widespread use of live attenuated vaccine, have sharply reduced the prevalence of measles and its related morbidity and mortality in many parts of the world. Additional attenuated vaccine preparations have been developed; though not fully evaluated, they appear to be safe and highly effective and to confer prolonged, if not lifelong, protection.

Despite the introduction of effective immunizing agents, measles continues to be a major public health concern. The continued occurrence of outbreaks of measles, especially among young adults, emphasizes the probable failure of herd immunity to eliminate measles transmission, despite high local immunization rates in young children. The outbreaks also indicate the possibility that a small number of appropriately immunized individuals may not develop solid immunity. It is estimated that about 700,000 to 800,000 people, mostly children, die of measles each year.

Measles vaccine is commercially available in live attenuated form and is used routinely in the MMR preparation for infant immunization at about 15 months of age. Susceptible older children or adults who have not had measles or have not previously received measles vaccine also should receive a single dose.

Mumps vaccine

Mumps is generally a self-limited disease in children but occasionally is moderately debilitating. A live attenuated mumps vaccine is available alone or in combination with measles and rubella vaccines. No serious adverse reactions have been reported following mumps immunization.

Pneumococcal vaccine

Streptococcus pneumoniae (pneumococcus) is the most frequent cause of bloodstream infection, pneumonia, and ear infection and is the third most common cause of bacterial meningitis in children. Pneumococcal infection is particularly serious among the elderly and among children with sickle-cell anemia, with congenital or acquired defects in immunity, without spleens, or with abnormally functioning spleens.

Immunity after pneumococcal disease is type-specific and lifelong. The pneumococcal vaccine now available consists of polysaccharide antigens from many of the most common types of pathogenic pneumococci. It can be given to children two years of age or older or to adults in a single intramuscular injection. The duration of protection is unknown.

Meningococcal vaccine

Neisseria meningitidis can cause meningitis (infection of the coverings of the brain and spinal cord) or severe bloodstream infection known as meningococcemia. In the general population, less than 1 per 400,000 persons is attacked by the bacterium, while among those younger than one year, the ratio rises to 1 per 100,000. In a day-care centre in which a primary case of meningococcal disease has occurred, the ratio has been reported at 2 to 100 per 100,000, and the danger from household contact from an infected person is believed to be 200 to 1,000 times greater than that of the general population. Because of these statistics, anyone who has had contact with the disease in a home, day-care centre, or nursery school should receive prophylactic antibiotic treatment as soon as possible, preferably within 24 hours of the diagnosis of the primary case of the disease.

Group-specific meningococcal polysaccharide vaccines can be used to control outbreaks of disease and may benefit travelers to countries where these diseases are endemic. Certain of the vaccines are administered routinely to military recruits in the United States.

Hepatitis B vaccine

Hepatitis B virus (HBV) produces an illness characterized by jaundice, poor appetite, malaise, and nausea. Chronic liver disease may follow the infection. Hepatitis B vaccine is recommended for infants and for persons who are at a greater risk of contracting the disease because of their lifestyles or jobs. These include health care personnel who are exposed to blood products, hemodialysis patients, institutionalized patients and their staffs, patients receiving multiple transfusions, prostitutes and the sexual partners of individuals with the disease, users of illicit intravenous drugs, and homosexual males.

Hepatitis B vaccine consists of recombinant viral surface antigen particles and is given in a three-dose series.

Influenza vaccine

The manufacture of influenza vaccine is complicated by the many influenza viruses and by the major changes in antigenic composition that these viruses continually undergo. Routine immunization against influenza viruses is recommended for all healthy individuals before the respiratory disease season commences (in the fall) and may be recommended throughout the year for travelers to a different hemisphere (e.g., from North to South America, because their winter seasons are reversed).

Haemophilus influenzae type B vaccine

The bacterium Haemophilus influenzae is a major cause of morbidity and mortality in children, particularly in those under six years of age. Because it is highly contagious among people in close contact with one another, antibiotics were traditionally used to prevent infection. In 1990 a powerful vaccine called a conjugate vaccine was licensed, and it has caused a dramatic decrease in H. influenzae disease in many countries.

Chickenpox (varicella) vaccine

The low morbidity of chickenpox in healthy children does not arguably support the universal use of vaccine. In certain persons, especially those with immunodeficiency disease or cancer, however, chickenpox can be devastating. A live attenuated vaccine has been found to be safe and immunogenic in healthy children and has recently been licensed, although its use has been questioned.

Passive immunity

Passive immunity is the administration of antibodies to an unimmunized person from an immune subject to provide temporary protection against a microbial agent or toxin. This type of immunity can be conferred on persons who are exposed to measles, mumps, whooping cough, poliomyelitis, rabies, rubella (German measles), tetanus, chickenpox, and herpes zoster (shingles). The process is also used in the treatment of certain disorders associated with bites (snake and spider) and as a specific (Rho-GAM) or nonspecific (antilymphocyte serum) immunosuppressant. Other antibody preparations are available under specific conditions for specific disorders. Passive immunization is not always effective; the duration of immunity provided is brief and variable, and undesirable reactions may occur, especially if the antiserum is of nonhuman origin. Several preparations are available for use as passive immunizing agents.

HISG

Human immune serum globulin (HISG) is prepared from human serum. Special treatment of the serum removes various undesirable proteins and infectious viruses, thus providing a safe product for intramuscular injection. HISG is used for the treatment of antibody deficiency conditions and for the prevention of hepatitis A and hepatitis B viral infections, measles, chickenpox, rubella, and poliomyelitis.

The most widespread use of HISG is in the prevention of hepatitis A infection, a disease for which active immunization has only recently become available, in individuals known to have had intimate exposure to the disease. Hepatitis B immunoglobulin should be given immediately to susceptible persons who are exposed to contaminated blood or who have had intimate physical contact with a person who has hepatitis B infection. Because of the scarcity of the product, hepatitis B immune globulin is not recommended routinely for those who are continuously at high risk of exposure to hepatitis B. It should be given, however, in conjunction with vaccination, to infants born to mothers who have serological evidence of hepatitis B viral infection.

Several investigators have claimed a beneficial effect of HISG in persons with HIV infection and AIDS, as well as in persons with asthma and other allergic disorders; evidence confirming its efficacy in these conditions is lacking, however. Monthly HISG is not beneficial in the prevention of upper respiratory infections, otitis, skin infections, gastrointestinal disorders, or fever of undetermined cause. HISG has been used inconclusively in the treatment of infants with significantly low levels of immunoglobulins and patients with severe burns who are at an increased risk of infection. Antivenoms derived from horses are used effectively to treat snake or spider bites, but not without significant risk of reaction to the equine antibody preparation.

Rho-GAM

Rho-GAM is a human anti-RhD immune serum globulin used in the prevention of Rh hemolytic disease of the newborn. Rho-GAM is given to Rh-negative mothers after the delivery of Rh-positive infants or after miscarriage or abortion to prevent the development of anti-Rh antibodies, which could cause hemolysis (red blood cell destruction) in the infant of a subsequent pregnancy.

Antitoxins

Botulism, a severe paralytic poisoning, results from the ingestion or absorption of the toxin of the bacterium Clostridium botulinum. As a preventive measure, antitoxin can be given to individuals known to have ingested contaminated food and to patients with symptoms as soon as possible after exposure.

Most of the damaging effect of diphtheria results from the toxin produced by the bacterium Corynebacterium diphtheriae. This toxin not only has local effects but also is distributed through the blood to the heart, nervous system, kidneys, and other organs. Diphtheria antitoxin of animal origin remains the principal treatment, along with antibiotics.

Gas gangrene is caused by infection with clostridial organisms, usually following a traumatic injury that has caused extensive local tissue damage. An antitoxin derived from horses is available as an adjunct to surgical and other treatment of these infections.